Congenital adrenal hyperplasia (CAH) describes a number of conditions arising from absence or impaired function of enzymes in the adrenal steroidogenic pathway. Over 95% of cases represent deficiencies in the 21-hydroxylase enzyme (21- OHD, ‘classical’ CAH), with abnormalities of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase and 20,22-desmolase deficiencies also being described (Fig. 19a).
The clinical features of CAH depend upon the genetic basis of the disorder in individuals. Thus, complete deletion of the 21-OH gene will produce the full-blown effects of CAH, whereas gene mutations may be responsible for lesser clinical features corresponding to impaired enzyme action. The clinical features of CAH can be surmised by consideration of the steroidogenic pathway. In classical 21-OHD with severe enzyme deficiency, androgen production is increased alongside decreased synthesis of cortisol and aldosterone, leading to the typical clinical features of a newborn with ambiguous genitalia. In females this is generally identified at birth, so that early treatment prevents the onset of salt-losing crisis secondary to mineralocorticoid deficiency. In male babies, this may present as failure to thrive, and subsequent vomiting, diarrhoea and circulatory collapse are the presenting clinical features. Milder variants of classical 21-OHD may present in childhood with virilization and precocious puberty. Those with ‘non-classical’ forms of the disease may not present until early adulthood, usually young women with irregular menses and hirsutism. Treatment of CAH is by glucocorticoid replacement therapy, thereby restoring the negative feedback in the pituitary–adrenal axis and lowering the ACTH drive to androgen production. In young women with non-classical CAH this may be combined with antiandrogen therapy.
The molecular genetics of CAH have been the subject of much investigation. Prenatal diagnosis can be offered to affected families, either by chorionic villous sampling in the early stages of pregnancy or later amniocentesis. Prenatal treatment with glucocorticoids can prevent the virilization of a female fetus.
Physiological actions of cortisol Physiologically, cortisol affects intermediary metabolism, the nervous system and some processes related to reproduction. It permits other chemical mediators to act and, overall, it enables the organism to survive under stress (Fig. 19b; Table 19.1).
Intermediary metabolism. Cortisol increases the synthesis of a number of enzymes which play key roles in hepatic gluconeogenesis. This is an anabolic action of cortisol. In adipose tissue (fat) and skeletal muscle, however, cortisol is catabolic, that is it causes a breakdown of body tissues in order to mobilize energy. In these tissues, glucose uptake is inhibited and another substrate for adenosine triphosphate (ATP) production is found through proteolysis in muscle and lipolysis in fat. The free fatty acids released from muscle and fat travel to the liver, where they are taken up and utilized as substrates for gluconeogenesis. The net result is increased glucose or hyperglycaemia.
Nervous system. Adrenocorticotrophic hormone (ACTH) and cortisol are synthesized and released in a diurnal rhythm (Fig. 19c). The rhythm is determined by the interaction with the external environment, particularly the light–dark cycle and sleep patterns, and this implicates the brain. The brain releases corticotrophin releasing hormone (CRH), which in turn releases ACTH, which stimulates gluco corticoid release. Glucocorticoids feed back to the anterior pituitary and hypothalamus to limit ACTH and CRH release, respectively, through their intracellular receptors and possibly through membrane gluco corticoid receptors. The application of the synthetic glucocorticoid dex- amethasone abolishes the CRH stimulation of ACTH. The diurnal rhythm of glucocorticoid secretion reflects a similar rhythm of ACTH secretion. The rhythms are regulated by a ‘biological clock’, which may reside in the suprachiasmatic area of the brain (Chapter 5). The mechanism that causes the rhythm is thus inbuilt, but may be synchronized by exogenous (outside) influences such as light. This is particularly important in the case of seasonal breeding animals, where day length may determine the onset and offset of reproductive activity.
Glucocorticoids influence neuronal development in the fetal and neonatal brain. Administration of glucocorticoids to neonatal rats results in a reduction in both the basal level and the diurnal rhythm of ACTH and glucocorticoid release in the adult. This suggests that endogenous glucocorticoids may play a part in the normal development of the CRH–ACTH axis. In the adult rat, adrenalectomy (removal of the adrenal gland) results in the loss of neurones in specific regions of the hippocampus, an area of the brain concerned with memory, learning and the functioning of the hypothalamic–pituitary systems. Concurrent administration of glucocorticoids with adrenalectomy prevents neuronal loss, suggesting that glucocorticoids help to maintain cellular and structural integrity in specific areas of the brain.
Permissive actions and stress. Glucocorticoids allow other hormones to exert certain effects. For example: they are required for catecholamine synthesis and reuptake into nerve; they enable the process of catecholamine-stimulated fat mobilization; and, through their effects on gluconeogenesis, they permit the body to maintain its temperature and its response to stress. The body’s response to stress has been termed the General Adaptation Syndrome (GAS). Three main phases have been postulated: (i) alarm reaction; followed by (ii) resistance; and then by (iii) exhaustion. The alarm reaction is the initial release of epinephrine from the adrenal medulla and the release of norepinephrine from sympathetic nerve terminals. At the same time, glucocorticoids are released, and these permit the catecholamines to act. Their onset of action is slower than that of the catecholamines, so they provide a continued resistance to stress. If stress is prolonged, this leads to exhaustion, characterized by muscle wasting, atrophy of tissues of the immune system, gastric ulceration, hyperglycaemia and vascular damage.